Biotechnology and Biomaterial-Based Therapeutic Strategies for Age-Related Macular Degeneration. Part I: Biomaterials-Based Drug Delivery Devices

Abstract

Age-related Macular Degeneration (AMD) is an up-to-date untreatable chronic neurodegenerative eye disease of multifactorial origin, and the main causes of blindness in over 65 years old people. It is characterized by a slow progression and the presence of a multitude of factors, highlighting those related to diet, genetic heritage and environmental conditions, present throughout each of the stages of the illness. Current therapeutic approaches, mainly consisting of intraocular drug delivery, are only used for symptoms relief and/or to decelerate the progression of the disease. Furthermore, they are overly simplistic and ignore the complexity of the disease and the enormous differences in the symptomatology between patients. Due to the wide impact of the AMD and the up-to-date absence of clinical solutions, the development of biomaterials-based approaches for a personalized and controlled delivery of therapeutic drugs and biomolecules represents the main challenge for the defeat of this neurodegenerative disease. Here we present a critical review of the available and under development AMD therapeutic approaches, from a biomaterials and biotechnological point of view. We highlight benefits and limitations and we forecast forthcoming alternatives based on novel biomaterials and biotechnology methods. In the first part we expose the physiological and clinical aspects of the disease, focusing on the multiple factors that give origin to the disorder and highlighting the contribution of these factors to the triggering of each step of the disease. Then we analyze available and under development biomaterials-based drug-delivery devices (DDD), taking into account the anatomical and functional characteristics of the healthy and ill retinal tissue.

Keywords: Bruch’s membrane; VEGF; biomaterials; nanocarriers; neuroprotection; ocular drug delivery; retina; retinal pigment epithelium.

FIGURE 1

Schematic representation of the eye and the stages of the AMD. (A) The eye and the retina. (B) Normal retina in a cross section of the eye where appear: the layer of the photoreceptors, the choroid, the RPE and the Bruch’s membrane (BrM). The main functions of the normal RPE are: (1) transport of nutrients, ions, and water (2) absorption of light and protection against photooxidation, (3) re-isomerization of all-trans-retinal into 11-cis-retinal, which is a key element of the visual cycle, (4) phagocytosis of shed photoreceptor membranes, and (5) secretion of various essential factors for the structural integrity of the retina. POS, photoreceptors outer segment; BRB, blood–retinal barrier; PEDF, pigment epithelium-derived factor, the most potent inhibitor of angiogenesis in the mammalian eye; VEGF, vascular endothelial growth factor. VEGF is essential for development and maintenance of functionally efficient retinal vasculature as well as for integrity of the RPE, BrM, and choroidal endothelial cells. (C) Early and intermediate AMD phases in a cross section of the eye. Without apparent cause, debris from the RPE cells layer as well as from the surrounding tissues begin to accumulate between RPE and BrM forming clusters called drusen. (D) Progress of the dry AMD in a cross section of the eye where the clusters called drusen start growing in size and accumulate as the disease progresses. The accumulation of drusen and the degeneration of RPE provokes the beginning of photoreceptor’s atrophy. (E) The progress of wet AMD. As drusen accumulate, they can cause inflammation. Inflammatory cells are then recruited by the retina, and these cells, together with the RPE begin to release vascular growth factors (mainly VEGF) that cause growth of the blood vessels. In this case, the degeneration is characterized by choroidal neovascularization, neovessels penetrating the BrM, presence of inflammatory cells, exudates of lipid content, hemorrhage, and the destruction of the RPE and photoreceptors (wet AMD).

FIGURE 2

Representative photographs of AMD-affected eyes. (A) Eye of a healthy subject; (B) AMD patient with macular hemorrhage and active exudation; (C) AMD patient with wide macular geographic atrophy and several druses in the back of the eye; (D) AMD patient with macular pigment changes, several druses as well as a macular hemorrhage secondary to an active neovascular complex; (E) patient with an active macular neovascular complex, secondary to an AMD; (F) AMD patient with an active AMD with a pseudo-tumoral lesion.

FIGURE 3

Developing strategies for the sustained drug delivery to the retina. We describe the type of systems that can be used to encapsulate the different molecules can be classified based on the size. The nano-formulations allows the encapsulation of the drugs directly to a molecule that favors the administration and the survival of the substance. The bulk systems protect the drug and allows a progressive administration of the substance during longer periods of time. And, we also represent the ideal characteristics of a sustained drug delivery platform for AMD.

FIGURE 4

Representation of the ocular drug delivery methods discussed on this review. The treatment of retinal diseases is challenging due to the anatomic barriers and physiological clearance mechanism of the eye. This figure represents the methods currently used in the clinical setting to treat posterior segments diseases classified by their administration route.